Whole body vibration ameliorates anxiety-like behavior and memory functions in 30 months old senescent male rats.

Whole body vibration (WBV) is a form of passive exercise that offers an alternative physical training to aged individuals with limitations in their physical and mental capabilities. The aim of the present study was to explore the therapeutic potential of five weeks of WBV on anxiety-like behaviors as well as learning and memory abilities in senescent thirty months old rats. Animals were exposed to 5 min vibration twice per day, five times per week during the five consecutive weeks. Pseudo WBV treated animals served as controls. After five weeks of WBV treatment, animals were tested for anxiety-like behavior by the open field test and for spatial and object memory functions by the novel and spatial object recognition tests, respectively. As a result, anxiety-like and exploratory behaviors were significantly improved in the WBV treated group compared to the pseudo WBV group. Furthermore, WBV treatment increased discrimination performance in both spatial and object memory function testing. These results indicate that WBV treatment in thirty months old rats seems to have comparable beneficial effects on age-related emotional and cognitive performance as what has been reported in younger age groups.

Eating habits modulate short term memory and epigenetical regulation of brain derived neurotrophic factor in hippocampus of low- and high running capacity rats.

Exercise capacity and dietary restriction (DR) are linked to improved quality of life, including enhanced brain function and neuro-protection. Brain derived neurotrophic factor (BDNF) is one of the key proteins involved in the beneficial effects of exercise on brain. Low capacity runner (LCR) and high capacity runner (HCR) rats were subjected to DR in order to investigate the regulation of BDNF. HCR-DR rats out-performed other groups in a passive avoidance test. BDNF content increased significantly in the hippocampus of HCR-DR groups compared to control groups (p<0.05). The acetylation of H3 increased significantly only in the LCR-DR group. However, chip-assay revealed that the specific binding between acetylated histone H3 and BNDF promoter was increased in both LCR-DR and HCR-DR groups. In spite of these increases in binding, at the transcriptional level only, the LCR-DR group showed an increase in BDNF mRNA content. Additionally, DR also induced the activity of cAMP response element-binding protein (CREB), while the content of SIRT1 was not altered. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was elevated in HCR-DR groups. But, based on the levels of nuclear respiratory factor-1 and cytocrome c oxidase, it appears that DR did not cause mitochondrial biogenesis. The data suggest that DR-mediated induction of BDNF levels includes chromatin remodeling. Moreover, DR does not induce mitochondrial biogenesis in the hippocampus of LCR/HCR rats. DR results in different responses to a passive avoidance test, and BDNF regulation in LCR and HCR rats.

Are the neuroprotective effects of estradiol and physical exercise comparable during ageing in female rats?

Ageing of the brain is accompanied by variable degrees of cognitive decline. Estrogens have profound effects on brain ageing by exerting neurotrophic and neuroprotective types of action. Furthermore, exercise has also been claimed to play a role in the non-pharmacological prevention of psycho-neuronal decline with ageing. In the present study the question was asked whether chronic physical exercise might substitute the action of estrogens in aged rats. We compared the effects of 17ß-estradiol (E2) treatment and long-term moderate physical exercise in ageing (15 months, early stage of ageing) and old (27 months) female rats, on cognitive functions and the relevant intracellular molecular signaling pathways in the hippocampus. Results showed that both treatments improved attention and memory functions of the 15 months old rats. Like E2, physical training enhanced the level of brain derived nerve growth factor and the activation of PKA/Akt/CREB and MAPK/CREB pathways. The treatments also enhanced the levels of synaptic molecules synaptophysin and synapsin I, which could explain the improved cognitive functions. In the 27 months old rats the behavioral and molecular effects of E2 were indistinguishable from those found in the 15 months old animals but the effects of physical exercise in most of the measures proved to be practically ineffective. It is concluded that the effectiveness of regular and moderate intensity physical exercise is age-dependent while the action of E2 treatment is comparable between the ageing and old female rats on maintaining cognition and its underlying molecular mechanisms.

Neuroprotective effects of estrogen treatment on ischemia-induced behavioural deficits in ovariectomized gerbils at different ages.

Although much is known about the protective effect of acute estrogen therapy in cerebral ischemia, relatively little is known about its effect on functional outcome at different ages. The impact of age is, however, important on the efficacy of steroids in the central nervous system. We investigated whether a single dose of estradiol pre-treatment would be neuroprotective in young (4 months), middle-aged (9 months) and old (18 months) female gerbils following 10min global brain ischemia. Apoptotic and necrotic cells were labelled and quantified in the affected hippocampus; exploratory activity, attention and memory functions were tested using open field, spontaneous alternation, novel object recognition and hole-board test. Age effect and treatment effect were analysed. High single dose (4mg/kg b.w.) of estradiol pre-treatment exposed a marked neuroprotective effect against hippocampal cell loss in all age groups. In behavioural tests, however, age-related differences could be observed. In middle-aged and old animals the worsening in memory function following ischemia was more prominent compared to that in the young ones. In the Y-maze and the novel object recognition tests the middle-aged, in the hole-board test (investigating working memory and total time) the old gerbils had the worst functional outcome. Only reference memory in hole-board test did not change by age. Estrogen improved memory performances in all the tests at every age. We can conclude that age of experimental animals is a factor worsening the outcome following brain ischemia. A single-dose estrogen therapy prevents the lesion-induced behavioural dysfunctions and the hippocampal cell loss.

Neuroprotective effects of vinpocetine and its major metabolite cis-apovincaminic acid on NMDA-induced neurotoxicity in a rat entorhinal cortex lesion model.

Vinpocetine (ethyl-apovincaminate, Cavinton), a synthetic derivative of the Vinca minor alkaloid vincamine, has been used now for decades for prevention and treatment of cerebrovascular diseases predisposing to development of dementia. Both vinpocetine and its main metabolite cis-apovincaminic acid (cAVA) exert a neuroprotective type of action. Bilateral N-methyl-D-aspartate (NMDA)-induced neurodegeneration in the entorhinal cortex of rat was used as a dementia model to confirm the neuroprotective action of these compounds in vivo. NMDA-lesioned rats were treated 60 min before lesion and throughout 3 postoperative days with a 10 mg/kg intraperitoneal dose of vinpocetine or cAVA. Behavioral tests started after termination of drug treatment and consisted of novel object recognition, social discrimination, and spontaneous alternation in a Y-maze, and spatial learning in the Morris water maze. At the end of behavioral testing brains were perfused with fixative and the size of the excitotoxic neuronal lesion and that of microglial activation around the lesion were assayed quantitatively on brain sections immunostained for neuron-specific nuclear protein (NeuN) and integrin CD11b, respectively. Entorhinal NMDA lesions impaired recognition of novel objects and the new social partner, and suppressed spontaneous alternation and spatial learning performance in the Morris maze. Both vinpocetine and cAVA effectively attenuated the behavioral deficits, and significantly decreased lesion size and the region of microglia activation. Both lesion-induced attention deficit and learning disabilities were markedly alleviated by vinpocetine and cAVA. The morphological findings corroborated the behavioral observations and indicated reduced lesion size and microglia activation especially after vinpocetine treatment which supports an in vivo neuroprotective mode of action of vinpocitine and a less potent action of cAVA.

Adopted cognitive tests for gerbils: validation by studying ageing and ischemia.

Transient occlusion of common carotid arteries in gerbils is a simple and widely used model for assessing histological and functional consequences of transient forebrain ischemia and neuroprotective action of pharmaceuticals. In the present study we aimed to introduce additional behavioural tests as novel object recognition and food-motivated hole-board learning in order to measure attention and learning capacity in gerbils. For validating these cognitive tests the effects of ageing (4, 9 and 18 months) and those of transient forebrain ischemia induced by bilateral carotid occlusion at 9 months of age were investigated. Neuronal cell death was estimated in the hippocampus using TUNEL and caspase-3 double fluorescence labelling and confocal microscopy. Ageing within the selected range although influenced ambulatory activity, did not considerably change attention and memory functions of gerbils. As a result of transient ischemia a selective neuronal damage in CA1 and CA2 regions of the hippocampus has been observed and tested 4 days after the insult. Ischemic gerbils became hyperactive, but showed decreased attention and impaired spatial memory functions as compared to sham-operated controls. According to our results the novel object recognition paradigm and the hole-board spatial learning test could reliably be added to the battery of conventional behavioural tests applied previously in this species. The novel tests can be performed within a wide interval of adult age and provide useful additional methods for assessing ischemia-induced cognitive impairment in gerbils.

Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference.

Chronic use of psychostimulants induces enduringly increased responsiveness to a subsequent psychostimulant injection and sensitivity to drug-associated cues, contributing to drug craving and relapse. Neurotensin (NT), a neuropeptide functionally linked to dopaminergic neurons, was suggested to participate in these phenomena. We and others have reported that SR 48692, an NT receptor antagonist, given in pre- or co-treatments with cocaine or amphetamine, alters some behavioral effects of these drugs in rats. However, its efficacy when applied following repeated cocaine administration remains unknown. We, therefore, evaluated the ability of SR 48692, administered after a cocaine regimen, to interfere with the expression of locomotor sensitization and conditioned place preference (CPP) in rats. We demonstrated that the expression of locomotor sensitization, induced by four cocaine injections (15 mg/kg, i.p.) every other day and a cocaine challenge 1 week later, was attenuated by a subsequent 2-week daily administration of SR 48692 (1 mg/kg, i.p.). Furthermore, the expression of cocaine-induced CPP was suppressed by a 10-day SR 48692 treatment started after the conditioning period (four 15 mg/kg cocaine injections every other day). Taken together, our data show that a chronic SR 48692 treatment given after a cocaine regimen partly reverses the expression of locomotor sensitization and CPP in the rat, suggesting that NT participates in the maintenance of these behaviors. Our results support the hypothesis that targeting neuromodulatory systems, such as the NT systems may offer new strategies in the treatment of drug addiction.

Dexamethasone downregulates chemokine receptor CXCR4 and exerts neuroprotection against hypoxia/ischemia-induced brain injury in neonatal rats.

OBJECTIVE: Hypoxia/ischemia (H/I) induces rapid and massive brain damage in neonatal rat brain, resulting in long-term consequences on structural and functional maturation of the central nervous system. Inflammatory mediators contribute to these permanent pathological changes, which are sensitive to corticoid treatments. Since the chemokine receptor CXCR4, specific for the SDF-1 alpha/CXCL12 ligand, regulates both apoptotic and neuroregeneration processes, this receptor was quantified 2 days following H/I in neonatal rat brain in relation with dexamethasone (DEX) treatment. METHODS: Seven-day-old male rats were exposed to a 90-min hypoxia following unilateral carotid ligation (H/I) and were sacrificed 48 h later. Glucocorticoid-pretreated animals were injected subcutaneously 5 h prior to hypoxia with 0.5 microg/g DEX. Glial fibrillary acidic protein and cresyl violet staining were used for assessing the extent of brain lesion subdivided into necrotic and penumbra-like areas. The density of CXCR4 receptors was determined by quantitative autoradiography using [(125)I]SDF-1 alpha as a ligand. RESULTS: The H/I resulted in a massive lesion ipsilateral to the carotid ligation, which was extended to cortical, striatal, hippocampal and thalamic areas, while the contralateral hemisphere remained apparently unaffected. DEX decreased the lesion size by reducing mainly the necrotic area. H/I induced a marked increase in CXCR4 receptor binding in the penumbra-like areas. DEX pretreatment decreased CXCR4 receptor density in the penumbra and attenuated astrocytosis. Furthermore, DEX strongly lowered mortality rate and reduced functional recovery time right after hypoxia. CONCLUSION: The rapid enhancement in CXCR4 chemokine receptor binding in the affected brain areas suggests that SDF-1 alpha/CXCR4 may play a role in the hypoxia-induced inflammatory reaction in the neonatal brain. Attenuation of CXCR4 expression and astrogliosis could contribute to the neuroprotective effect of DEX pretreatment via influencing the inflammatory cascade induced by H/I in the neonatal brain.